Introduction
Cancers, of varied etiology, affect billions of animals and humans each year and inflict an enormous economic burden on society. Cancers can be defined as an abnormal lump, mass of tissue, or cancerous cells generated from excessive cell division, which is either benign or malignant. Cancers include all those cancers known to physicians of ordinary skill in the medical arts, particularly physicians of skill in oncology. Cancers include, but are not limited to, those arising from ectodermal, mesodermal and endodermal cells and include cancers of the immune system, the endocrine system, the central nervous system, the respiratory system, the reproductive system, the gastrointestinal system, and the integument. Such cancers include those generated by AIDS-related cancers, adrenocortical cancer, anal cancer, bladder cancer, bowel cancer, brain and central nervous system cancers, breast cancer, carcinoid cancers, cervical cancer, chondrosarcoma, choriocarcinoma, colorectal cancer, endocrine cancers, endometrial cancer, Ewing's sarcoma, eye cancer, gastric cancer, gastrointestinal cancer, genitourinary cancers, glioma, gynecological cancer, head and neck cancer, hepatocellular cancer, Hodgkin's disease, hypopharyngeal cancer, islet cell cancer, Kaposi's sarcoma, kidney cancer, laryngeal cancer, leukemia, liver cancer, lung cancer, lymphoma, melanoma, basal cell carcinoma, mesothelioma, myeloma, nasopharyngeal cancer, neuroblastoma, non-Hodgkin's lymphoma, esophagael cancer, osteosarcoma, ovarian cancer, pancreatic cancer, pituitary cancer, renal cell carcinoma, prostate cancer, retinoblastoma, rhabdomyosarcoma, sarcoma, skin cancer, squamous cell carcinoma, stomach cancer, testicular cancer, thymus cancer, thyroid cancer, transitional cell cancer, trophoblastic cancer, uterine cancer, vaginal cancer, Waldenstrom's macroglobulinemia, Wilm's cancer, among other tumors and forms of cancer.
As with normal cells, cancer cells contain lipid as a major component of the plasma membrane that surrounds them. While it is not fully known why cancer cells form, in general, cancers appear to be caused by the abnormal regulation of cell division. This could be caused by abnormalities of the immune system, genetic abnormalities, radiation-caused mutations, certain viruses, sunlight, and cancer-causing agents such as tobacco, benzene, and other chemicals. When a patient is inflicted with a cancer, he incurs a number of symptoms, including fevers, chills, night sweats, weight loss, loss of appetite, fatigue, malaise, shortness of breath, chest pain, diarrhea, blood in the stool or urine, among other ailments.
Eliminating cancer from a patient's body is challenging because, although cancerous cells proliferate in an uncontrolled manner, the cells do not necessarily appear to be “foreign” to the body and, therefore, are difficult to target. Existing cancer treatments tend to be non-sufficiently targeted to the cancer cells and, therefore, are very destructive to a patient's healthy tissue. Such treatments include X-rays, chemotherapy, proton therapy, surgery or combinations thereof. It would be preferred if the body's immune system could be incited to exhibit a positive immune response against these cancer cells.
The human immune system is composed of various cell types that collectively protect the body from different foreign agents. The immune system provides multiple means for targeting and eliminating foreign elements, including humoral and cellular immune responses, participating primarily in antigen recognition and elimination. An immune response to foreign elements requires the presence of B-lymphocytes (B cells) or T-lymphocytes (T cells) in combination with antigen-presenting cells (APC), which are usually macrophages or dendrite cells. The APCs are specialized immune cells that capture antigens. Once inside an APC, antigens are broken down into smaller fragments called epitopes—the unique markers carried by the antigen surface. These epitopes are subsequently displayed on the surface of the APCs and are responsible for triggering an antibody response in defense of foreign agents.
In a humoral immune response, when an APC displaying antigens (in the form of unique epitope markers) foreign to the body are recognized, B cells are activated, proliferate and produce antibodies. These antibodies specifically bind to the antigens present on the APC. After the antibody attaches, the APC engulfs the entire antigen and kills it. This type of antibody immune response is primarily involved in the prevention of various infections.
In a cellular immune response, on recognizing the APC displaying a foreign antigen, the T cells are activated. There are two steps in the cellular immune response. The first step involves activation of cytotoxic T cells (CTL) or CD8+ T killer cells that proliferate and kill target cells that specifically represent the antigens presented by APC. The second involves helper T cells (HTL) or CD4+ T cells that regulate the production of antibodies and the activity of CD8+ cells. The CD4+ T cells provide growth factors to CD8+ T cells that allow them to proliferate and function efficiently.
While cancer cells are now known to express cancer-associated antigens, they are often able to evade an immune response because of their ability to hide cancer antigens from the immune system and/or because the exposed antigens are normal, nonmutated differentiation molecules or proteins which the human immune system normally recognizes or tolerates. To effectively use immunotherapy to treat a cancer, a patient must have, or be provided with, a sufficient number of cancer-reactive lymphocytes, which can both reach the cancer site and have effector mechanisms to destroy the cancer cells.
To date, immune responses generated by cancer vaccines have been unable to overcome the escape mechanisms of cancers, including the ability to target and infiltrate cancers, to deal with the loss of antigenic expression by the cancer, to handle the inability of the cancer to activate anti-cancer precursors, and to address the local presence of immunosuppressive factors. Some success has been observed in cell-transfer therapies where autologous lymphocytes are sensitized to cancer cells ex vivo and then infused back into the patient.
One adjuvant for cancer vaccine immunotherapy uses dendritic cells (DC) that are highly potent antigen-presenting cells to provoke a positive anti-cancer immune response in patients. Dendritic cells express MHC class I and MHC class II molecules, co-stimulatory molecules and adhesion molecules that provide signals for the stimulation of naive T cells, CD4+ T-helper cells, CD8+ cytotoxic T lymphocytes (CTLs), natural killer (NK) and thymic derived NK cells (NKT) cells. DC have the capacity to take up various types of molecules. Consequently, DC can be loaded with tumor-associated antigens (TAAs) in various forms and administered as vaccines.
One DC-based approach uses DC-cancer cell hybrids generated by fusion of cancer cells with DC to combine sustained cancer antigen expression with the antigen-presenting and immune stimulatory capabilities of DC. In animal models, immunization with DC-cancer cell hybrids can provide some form of anti-cancer protection or eradicate established disease. Hybrids of autologous DC comprised of cancer cell lines or primary human cancer cells (including breast carcinoma cells) have been shown to induce CTL responses against autologous cancer cell types in vitro. Recent phase I clinical trials for the treatment of renal cell carcinoma and glioma have demonstrated that vaccination with DC-cancer cell hybrids can safely induce anti-cancer immune responses in patients. Traditional fusion technology using polyethylene glycol (PEG) is hampered by a lack of reproducibility and difficulties in method standardization. As an alternative, electrofusion has been used for production of DC-cancer cell hybrids.” See Akporiaye, et al., “Pre-Clinical Studies of Dendritic Cell-Tumor Cell Fusion Vaccines to Treat Breast Cancer”.
Accordingly, what is needed is an effective delipidation process via which a cancer cell is modified, rather than destroyed, and invokes an autologous or heterologous immune response to prevent further proliferation of cancers.
What is needed is a therapeutic method and system for providing patients with modified cancer cells capable of initiating a protective immune response.
What is further needed is a way of identifying and revealing tumor-associated antigens that can be used with existing DC-cancer cell therapy techniques to provoke a positive immune response in a patient.
What is needed is a method for promoting antibody production comprising administering to a patient a modified cancer cell capable of initiating a protective immune response.